The proposed pilot study aims to be the first step in developing a novel treatment strategy of inducing moderate hyperbilirubinemia for preventing the vascular complications of type 1 diabetes mellitus (T1DM). Oxidative stress, defined as an excess of oxidants relative to antioxidants, in large part drives the vascular complications of T1DM. Bilirubin, long thought of as metabolic waste, is now recognized to have significant antioxidant properties. In addition to reducing oxidants, bilirubin directly inhibits the NADPH oxidase enzyme that is the major contributor to vascular oxidant stress in diabetes. Raising bilirubin levels therefore has the potential to not only increase antioxidant capacity but also directly inhibit oxidant generation. The proposed study will employ the drug atazanavir to induce hyperbilirubinemia. Atazanavir is approved for the treatment of HIV infection. It inhibits the hepatic enzyme responsible for bilirubin conjugation and therefore clearance, resulting in higher bilirubin levels. The proposed study will obtain preliminary data on the effects of induced moderate hyperbilirubinemia on endothelial function, antioxidant capacity, and oxidant stress in T1DM . Endothelial function is a reflection of the health of the inner lining of the blood vessels. Measuring endothelial function provides information about cardiovascular risk. Increased bilirubin levels could plausibly benefit endothelial function by lessening vascular oxidative stress. Specific Aim: To establish the feasibility of studying the change in endothelial function caused by induced moderate hyperbilirubinemia in type 1 diabetes mellitus. Atazanavir, a drug that inhibits bilirubin conjugation, will be used to induce moderate hyperbilirubinemia. Endothelial function will be measured before and after atazanavir therapy. In addition, plasma markers of antioxidant capacity and oxidant stress will be measured as proof-of-concept that induced moderate hyperbilirubinemia has favorable effects on oxidative stress in type 1 diabetes. We will study 20 subjects with T1DM in an open label, single arm intervention study of atazanavir 400 mg once daily x 8 days. Bilirubin and endothelial function will be measured on study days 4 and 8. If this pilot is successful, a controlled study of the effects of hyperbilirubinemia on endothelial function in T1DM would follow. Ultimately the goal is to conduct a large clinical trial of the effect of hyperbilirubinemia on cardiovascular events in type1 diabetes mellitus. PUBLIC HEALTH RELEVANCE: Type 1 diabetes mellitus ('juvenile diabetes') has a high risk of heart disease. This proposal hopes to show that it is possible in type 1 diabetes to reduce the risk of heart disease by using a medicine that is currently available but not yet considered a treatment for diabetes. The way this medicine works is that it raises bilirubin levels in the blood and bilirubin may protect the heart and blood vessels from damage due to diabetes.